Project Summary Despite the growing prevalence of Alzheimer?s disease (AD) the underlying mechanism by which its earliest clinical symptoms, deficits in new learning, are established remains poorly understood. Amyloid beta peptides (Ab), proteins that are among the earliest markers of AD, are compelling candidates for triggering these learning deficits; yet how Ab peptides alter neural circuits to compromise learning remains unclear. Our recent work identifies Nogo receptors, known inhibitors of synaptic plasticity and growth, as mediators of Ab dependent inhibition of new synapse assembly. Further, this work defines T-type calcium channels as targets inhibited by Ab-NgR signaling along the dendrite, resulting in calcium dysregulation, plasticity deficits and synapse loss We hypothesize that Ab-NgR mediated inhibition of T-type channels drives learning deficits by blocking new spine assembly. We will test this model by determining how NgR signaling mediators compromise synapse assembly (aim 1), by assessing if NgR signaling contributes to pathogenic drives of familiar AD (aim 2) and by targeting Ab-NgR signaling mediators in vivo to test the significance of their contributions to Ab-mediated synaptic and learning deficits. This study harnesses the power of live imaging based approaches in concert with electrophysiology and behavioral analysis to target Ab-NgR signaling in vivo, providing potentially compelling cause-and-effect evidence of the therapeutic potential of targeting this pathway in the treatment of AD in the future. !